Targeted therapy for renal cell carcinoma: a new therapeutic paradigm

Renal cell carcinoma is the most common tumor of the kidney. It has an unpredictable behavior and poor response to systemic therapy. Developing newer therapy for this disease is a priority considering the high recurrence rate and the small subset of patients who benefit from the use of cytokines such as interferon-alpha or interleukin-2. Identifying molecular targets and targeting various biomarkers has revolutionized the therapeutic approach to advanced and metastatic renal cell carcinoma. Although some of the antiangiogenic agents and receptor tyrosine kinase inhibitors appear promising, further understanding of their mechanism of action and the patient population who would benefit most from such agents is still being explored. As numerous targeted agents are entering the clinical investigation arena in a relatively short period of time, newer challenges in renal cell carcinoma therapeutics are emerging. Some of the future challenges in using targeted antineoplastic agents in renal cell carcinoma will include evaluating their long-term safety and benefit, using the particular drug in the appropriate patient population after appropriate stratification and studying the combination of some of these drugs for synergy or additive effects.     

Dendritic cell vaccination with MAGE peptide is a novel therapeutic approach for gastrointestinal carcinomas.

The MAGE gene is selectively expressed in cancer tissues such as melanoma or gastrointestinal carcinomas, whereas no expression is observed in normal tissues except testis. There are several reports of successful induction of HLA class I-restricted antitumor CTLs using MAGE peptides, and some clinical trials with these immunogenic peptides were reported as effective for some patients with malignant melanoma. However, there are no similar studies in gastrointestinal carcinomas, which are important neoplasms. Autologous dendritic cells (DCs) were generated ex vivo and were pulsed with MAGE-3 peptide, depending on the patient's HLA haplotype (HLA-A2 or A24). Patients were immunized with DC pulsed with MAGE-3 peptide every 3 weeks at four times. Twelve patients with advanced gastrointestinal carcinoma (six stomach, three esophagus, and three colon) were treated, and no toxic side effects were observed. Peptide-specific CTL responses after vaccination were observed in four of eight patients. Improvement in performance status was recognized in four patients. Tumor markers decreased in seven patients. In addition, minor tumor regressions evidenced by imaging studies were seen in three patients. These results suggested that DC vaccination with MAGE-3 peptide is a safe and promising approach in the treatment of gastrointestinal carcinomas.     

靶向药物治疗晚期肾癌的meta分析

目的:系统评价靶向药物治疗晚期肾癌的有效性和安全性。方法:计算机检索PubMed、EMBASE、Cochrane Library、中国期刊全文数据库(CNKI)、中国生物医学文献数据库(CBMdice)等,同时追查纳入的参考文献,收集靶向药物治疗晚期肾癌的随机对照试验。根据Cochrane Handbook 5.0的质量评价标准评价,采用RevMan 5.0软件进行统计学分析。结果:最终纳入5个随机对照试验,共2946例患者。meta分析结果显示,与干扰素相比,靶向药物单药虽未能提高晚期肾癌的有效率,却显著提高了晚期肾癌的疾病控制率(OR=2.89,95%CI:2.22-3.77,P<0.001)。靶向药物联合干扰素不但显著提高了晚期肾癌的疾病控制率(OR=2.14,95%CI:1.70-2.69,P<0.00001),还显著提高了有效率(OR=2.52,95%CI:1.90-3.33,P<0.00001)。与干扰素相比,靶向药物的不良反应明显增加,尤以3/4级心血管不良事件(OR=6.29,95%CI:1.77-22.27,P=0.004)、3/4级皮肤不良事件(OR=8.28,95%CI:3.91-17.56,P<0.0001)以及重度疼痛(OR=2.41,95%CI:1.38-4.24,P=0.002)的发生率增加最为明显。靶向药物与干扰素联用组的3/4级胃肠道反应(OR=2.08,95%CI:1.56-2.78,P<0.00001)、心血管(OR=8.67,95%CI:1.86-40.41,P=0.006)不良事件以及疲劳、无力等全身症状(OR=1.48,95%CI:1.20-1.83,P=0.0002)的发生率显著高于干扰素组。结论:与干扰素相比,靶向药物单用能更有效地控制晚期肾癌的进展,靶向药物联合干扰素可进一步提高疗效,是晚期肾癌较好的解救方案,但也伴随更多不良反应的发生。     

Selecting targeted therapies for patients with renal cell carcinoma

Advanced renal cell carcinoma (RCC) is a heterogeneous disease with variable histology, biology, and response to treatment. In the past 5 years, 6 new agents have been approved for the treatment of RCC, and many more are in clinical development. With an ever-increasing number of treatment options, selecting among them for a particular patient can be a daunting task for clinicians. This article describes how treatment choice can be guided by the disease setting and histology, as well as patient characteristics, comorbidities, and preference within the context of available data. Results from clinical trials are combined with practical considerations to make recommendations for first-line and subsequent treatment of patients with clear cell and non-clear cell RCC. These recommendations should supplement the current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the treatment of advanced RCC.     

A novel peptide specifically binding to nasopharyngeal carcinoma for targeted drug delivery

Nasopharyngeal carcinoma (NPC) is a common cancer among Chinese living in southern China, Taiwan, and Singapore. The 5-year survival rate in the early stage of NPC has been reported as high as 90 to 95% with the use of radiotherapy, but in the advanced cases, even with the use of both chemotherapy and radiotherapy, the survival rate is still <50%. To improve the survival rate, we identify a 12-mer peptide (L-peptide) specifically binding to NPC cells with a phage displayed random peptide library. The L-phage and synthetic L-peptide bound to the tumor cell surfaces of most NPC cell lines and biopsy specimens, but not normal nasal mucosal cells, and the L-peptide-linked liposomes containing fluorescent substance (L-peptide-Lipo-HPTS) were capable of binding to and translocating across plasma membranes. L-Peptide-linked liposomes that carried doxorubicin (L-peptide-Lipo-Dox) caused marked cytotoxicity in NPC cells. In SCID mice bearing NPC xenografts, the L-phages specifically bound to the tumor mass, an effect that was inhibited by competition with synthetic L-peptide. In addition, the L-peptide-Lipo-Dox suppressed tumor growth better than Lipo-Dox. These results indicate that the novel L-peptide specifically binds NPC cells and is a good candidate for targeted drug delivery to NPC solid tumors.     

Limited benefit of targeted molecular therapy for inferior vena cava thrombus associated with renal cell carcinoma

Background

The clinical benefit of targeted molecular therapy (TMT) for an inferior vena cava (IVC) tumor thrombus associated with renal cell carcinoma (RCC) is unclear. The aim of the present study was to assess the change in IVC thrombus height during TMT and to identify the factors associated with the effect of TMT on an IVC thrombus in RCC patients.

Methods

The present study retrospectively analyzed 21 patients with an IVC thrombus who were treated with TMT at our hospital. Thrombus height and level before and after TMT were assessed using CT or MRI. Furthermore, we examined the factors associated with the effect of TMT on the IVC thrombus.

Results

The tumor thrombus level before TMT was I in 2 patients (10%), II in 10 (47%), III in 4 (19%), and IV in 5 (24%). Following TMT, the tumor thrombus height decreased in 16 patients (76%), and the mean decrease was 17 mm. The tumor thrombus height increased in 5 patients (24%), and the mean increase was 30 mm. The tumor thrombus level decreased in 4 patients (19%), remained stable in 15 patients (71%), and increased in 2 patients (10%). We found that the clinical nodal stage (p = 0.025) was significantly associated with and the serum neutrophil count (p = 0.067) tended to be associated with the reduction in the IVC thrombus.

Conclusion

The clinical benefit of TMT for an IVC thrombus associated with RCC is limited.

     

Eg5 inhibitor,a novel potent targeted therapy,induces cell apoptosis in renal cell carcinoma

Eg5 is critical for mitosis and overexpressed in various malignant tumors, which has now been identified as a promising target in cancer therapy. However, the anti-cancer activity of Eg5 inhibitor in renal cell carcinoma (RCC) remains an open issue. In this paper, we evaluated, for the first time, the therapeutic benefit of blocking Eg5 by S-(methoxytrityl)-l-cysteine (S(MeO)TLC) in RCC both in vitro and vivo. The expression of Eg5 was examined in clinical tissue samples and various kidney cell lines, including 293T, 786-0, and OS-RC-2. The anti-proliferative activity of Eg5 inhibitors, (S)-trityl-l-cysteine (STLC) and S(MeO)TLC, was evaluated by a cell viability assay. An apoptosis assay with Hoechst nuclear staining and flow cytometry was applied to investigate the efficacy of the S(MeO)TLC, which is more potent than STLC. Immunofluorescence was used to research the possible mechanism. Furthermore, in vivo studies were performed by using subcutaneous xenograft models, which were used to confirm its role as a potential anti-neoplastic drug. The Eg5 expression was detected in kidney cell lines and RCC tissues, which was low in normal kidney samples. STLC and S(MeO)TLC exhibited their optimal anti-proliferative activity in 72 h, and cells treated with S(MeO)TLC presented characteristic monoastral spindle phenotype in 24 h and apoptotic cells in 48 h. In vivo, S(MeO)TLC effectively suppressed tumor growth in subcutaneous xenograft models. Inhibition of Eg5 represses the proliferation of RCC in vitro and in vivo. All these findings collectively demonstrate that S(MeO)TLC, a potent Eg5 inhibitor, is a promising anti-cancer agent for the treatment of RCC.     

Renal cell carcinoma: new developments in molecular biology and potential for targeted therapies

Renal cell carcinoma (RCC) affects 38,000 individuals in the U.S. yearly. Seventy-five percent of cases are clear-cell carcinomas, and a majority is driven by dysfunction of the von Hippel-Lindau (VHL) gene. VHL loss of function and other non-VHL pathways leading to RCC share aberrant activation of the hypoxic response, such as upregulation of vascular endothelial growth factor (VEGF) and consequent neoangiogenesis. Metastatic RCC has been notoriously resistant to therapy. For decades, its treatment has been based on nephrectomy and limited use of toxic and often inefficient immunotherapy with interleukin-2 or interferon-alpha. However, new biologic agents are beginning to break the resistance barrier. Small-molecule multikinase inhibitors that target VEGF receptors (sunitinib and sorafenib) have a favorable toxicity profile and can prolong time to progression and preserve quality of life when used in newly diagnosed or previously treated patients. The anti-VEGF antibody bevacizumab enhances the response rate and prolongs disease control when added to interferon-alpha. Temsirolimus, a mammalian target of rapamycin inhibitor, prolongs the survival duration of patients with poor-risk disease. Despite three new drugs being approved for RCC in the past 2 years, responses are mostly partial and of limited duration. Multiple new drugs and drug combinations are undergoing clinical trials and will likely impact the treatment of RCC in future years. Compounds found to be active in the metastatic setting are now being tried in earlier stage disease in an attempt to improve curability. However, no method has yet been validated to predict patient response to these newer treatments.     

Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma

Background:

Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3β positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF-κB)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3β and to assess the anti-cancer effect of GSK-3β inhibition in RCC.

Methods:

Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3β in human RCCs. We used small molecule inhibitor, RNA interference, western blotting, quantitative RT–PCR, BrDU incorporation and MTS assays to study the effect of GSK-3β inactivation on renal cancer cell proliferation and survival.

Results:

We detected aberrant nuclear accumulation of GSK-3β in RCC cell lines and in 68 out of 74 (91.89%) human RCCs. We found that pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of renal cancer cells. We observed that inhibition of GSK-3 results in decreased expression of NF-κB target genes Bcl-2 and XIAP and a subsequent increase in renal cancer cell apoptosis. Moreover, we show that GSK-3 inhibitor and Docetaxel synergistically suppress proliferation and survival of renal cancer cells.

Conclusions:

Our results show nuclear accumulation of GSK-3β as a new marker of human RCC, identify that GSK-3 positively regulates RCC cell survival and proliferation and suggest inhibition of GSK-3 as a new promising approach in the treatment of human renal cancer.     

A novel inflammation-associated prognostic signature for clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) are typically situated in a complex inflammatory and immune microenvironment, which has been reported to contribute to the unfavorable prognosis of patients with ccRCC. There would be beneficial clinical implications for elucidating the roles of its molecular characteristics in the inflammatory microenvironment. This is because it would facilitate the development of reliable biomarkers for pre-stratification prior to the designation of individualized treatment strategies. In the present study, RNA-sequencing data from 607 patients were retrospectively analyzed to elucidate the profile of inflammatory molecules. Based on this, an inflammatory prognostic signature (IPS) was developed and further validated using clinical ccRCC samples. Subsequently, the associated mechanisms in terms of the immune microenvironment and molecular pathways were then investigated. This proposed IPS was found to exhibit superior accuracy compared with the criterion of a good prognostic model for the prediction of patient prognosis from ccRCC [area under the receiver operating characteristic curve (AUC)=0.811] in addition to being an independent factor for prognostic risk stratification [hazard ratio: 11.73 (95% CI, 26.98-5.10); log-rank test, P<0.001]. Pathologically, ccRCC cells identified as high-risk according to their IPS presented with a more malignant tumor structure, including voluminous eosinophilic cytoplasm, acinar/lamellar/tubular growth patterns and atypic nuclei. High-risk ccRCC also exhibited higher infiltration levels by four types of immune cells, including T regulatory cells, but lower infiltration levels by mast cells. Pathways associated with immune-inflammation interaction, including the IL-17 pathway, were found to be upregulated in IPS-identified high-risk ccRCC. Furthermore, by combining the IPS with clinical factors, an integrated prognostic index was developed and validated for increasing the accuracy of patient risk-stratification for ccRCC (AUC=0.911). In conclusion, the complex regulatory mechanisms and molecular characteristics involved in ccRCC-inflammation interaction, coupled with their prognostic potential, were systematically elucidated in the present study. This may have important implications in furthering the understanding into the molecular mechanisms underlying this ccRCC-inflammation interaction, which can in turn be exploited for identifying high-risk patients with ccRCC prior to designing their clinical treatment strategy.     

NCCN Task Force report: optimizing treatment of advanced renal cell carcinoma with molecular targeted therapy

The outcome of patients with metastatic renal cell carcinoma has been substantially improved with administration of the currently available molecularly targeted therapies. However, proper selection of therapy and management of toxicities remain challenging. NCCN convened a multidisciplinary task force panel to address the clinical issues associated with these therapies in attempt to help practicing oncologists optimize patient outcomes. This report summarizes the background data presented at the task force meeting and the ensuing discussion.     

Challenges and opportunities for converting renal cell carcinoma into a chronic disease with targeted therapies

Optimum efficacy is the primary goal for any cancer therapy, and entails controlling tumour growth and prolonging survival as far as possible. The prognosis for patients with metastatic renal cell carcinoma (mRCC) has greatly improved with the introduction of targeted therapies. This review examines the development and efficacy of targeted agents for the management of mRCC, the challenges offered by their rapid emergence, and discusses how mRCC treatment may evolve in the future. Improvements in progression-free survival and overall survival rates, observed with targeted agents, indicate that it may now be possible to change mRCC from a rapidly fatal and largely untreatable condition into a chronic disease. The major challenges to further advances in targeted therapy for mRCC include overcoming drug resistance, identifying the most effective sequence or combination of targeted agents, optimising clinical trial design and managing the cost of treatment.     

A novel approach of targeted ablation of mammary carcinoma cells through luteinizing hormone receptors using Hecate-CGbeta conjugate

Recent studies have shown that human and animal mammary gland carcinoma cell line express luteinizing hormone receptors (LHRs). We have examined the cytotoxic effect of Hecate-CG conjugate, that is, fusion of a lytic peptide (Hecate) and a 15-amino acid fragment of the CG-chain in vitro. To test the hypothesis that the Hecate-CG conjugate selectively abolishes cells possessing LHR, estrogen dependent and independent human breast cancer cell lines (MCF-7; MDA-MB-231) and a mouse Leydig tumor cell line (BLT-1) were treated in vitro with Hecate-CG conjugate and Hecate alone. Cytotoxic effects of the Hecate-CG conjugate and the Hecate alone was measured by lactate dehydrogenase (LDH) release immediately after treatment. We observed that the Hecate-CG conjugate selectively, in dose-dependent manner destroys cells possessing LHR in lower concentrations of preparate comparing to the Hecate alone and that the cytotoxic effect is strongly correlated with the number of LHR. Using Western blot analysis we characterized the LHR on membranes of MDA-MB-231, MCF-7 and BLT-1 tumor cell lines. In addition, we showed the evaluation of inhibition potential of the Hecate-CG conjugate to LHR. At a concentration of 33 µM the conjugate inhibited (50%; IC₅₀) the binding of CG to LHR.We suggest further development of this novel approach for the treatment of breast cancer by the Hecate-CG for in vivo trials.     

Gonadotropin hormone-releasing hormone analogues: a new therapeutic approach for prostatic carcinoma

The introduction of potent analogues of gonadotropin hormone-releasing hormone (GnRH) into clinical practice and their use in patients with metastatic prostatic carcinoma provides an effective alternative to the exogenous administration of pharmacologic doses of estrogens or surgical castration. Their advantages over estrogens are primarily related to a lower incidence of cardiovascular toxicity and gynecomastia. Their choice over orchiectomy is based on cosmetic and psychologic factors since their endocrine effects and clinical benefits are virtually the same. In this review, we describe the current experience with GnRH analogues in the treatment of prostatic carcinoma and discuss their use in the context of other endocrine manipulations. GnRH analogues act on the pituitary and indirectly affect gonadal function, and represent an opportunity for combination with other compounds capable of suppressing or interfering with the effects of circulating and androgens. The availability of several new compounds affecting different aspects of androgen metabolism provides promise for rational drug selection and testing.     

Prognostic factors for survival in patients with metastatic renal cell carcinoma treated with targeted therapies

Background:

The most important prognostic factors for survival in patients with metastatic renal cell carcinoma (mRCC) were evaluated in the era of cytokine therapy, and only recently were revalidating in patients receiving targeted therapies (TTs).

Methods:

Clinical data for consecutive patients with mRCC who received TTs were retrieved from the database of Istituto Nazionale dei Tumori of Milan. Variables with a significant association with overall survival (OS) were estimated by proportional hazard regression, and a backward stepwise multivariate analysis identified the independent prognostic factors.

Results:

Data for 336 consecutive patients treated with TTs for RCC during the period 2004–2011 were evaluated. According to the Motzer classification, 32% patients were low risk, 48% were intermediate risk and 20% were poor risk. One hundred and sixty-seven (49.7%) patients received one TT, 116 (34.5%) received a second-line TT, 42 (12.5%) a third-line TT and 11 (3.3%) patients received a fourth-line TT. The median OS was 24 months (95% CI 20.0, 27.0) and the 5-year OS rate was 24.6% (95% CI 18.7, 30.8%). In the uni- and multivariate analysis Motzer risk classification, Fuhrman grade and previous cytokine therapy were identified as independent prognostic factors (P<0.01).

Conclusion:

The Motzer classification was confirmed as an independent prognostic factor for OS in patients with mRCC receiving TTs. Additionally, Fuhrman grade and previous cytokine therapy were independent prognostic factors for clinical outcome.     

Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy

BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is up-regulated in many human cancers, and agents targeting the mTOR pathway are in various stages of clinical development. The goal of the study was to evaluate the potential and limitations of targeting the mTOR pathway in renal cell carcinoma (RCC). METHODS: Immunohistochemical analysis using antibodies against pAkt, PTEN, p27, and pS6 was performed on a tissue microarray constructed from paraffin-embedded specimens from 375 patients treated by nephrectomy for RCC. The expression was associated with pathological parameters and survival. RESULTS: The mTOR pathway was more significantly altered in clear-cell RCC, high-grade tumors, and tumors with poor prognostic features. PS6 and PTEN showed the strongest associations with pathological parameters. Survival tree analysis regarding expression of cytoplasmic pAkt, nuclear pAkt, PTEN, cytoplasmic p27, and pS6 identified staining percentages of 40%, 10%, 75%, 7%, and 70%, respectively, as ideal cutoff values for stratification, with corresponding P-values of .03, .001, .02, .005, and <.0001, respectively. Interestingly, high nuclear pAkt expression was associated with a favorable prognosis, whereas high cytoplasmic pAkt expression was associated with a poor prognosis. In multivariate Cox regression analysis, ECOG PS, T classification, N classification, M classification, cytoplasmic Akt, nuclear pAkt, PTEN, and pS6 were independent prognostic factors of DSS. CONCLUSIONS: Components of the mTOR pathway are significantly associated with pathological features and survival. Not all RCC tumor types seem to be equally amenable to mTOR targeted therapy. PTEN, pAkt, p27, and pS6 may serve as surrogate parameters for patient selection and predicting prognosis. Patients with a highly activated mTOR pathway should benefit most from this therapy. External validation of our results is recommended.